Glutaminase is a key player in the altered metabolic pathways of tumor cells. The high glutamine requirements and uptake of cancer cells has been known for decades. For instance, in 1955, Eagle, in his paper “Nutrition needs of mammalian cultured cells” reported that glutamine, a non-essential amino acid, is quite essential for the growth of tumor cells in culture media. Since that report, research in tumor cell metabolism has revealed that high glutamine utilization and dependence, a property termed “glutamine addiction”, is a key attribute for multiple tumor cell lines.
There are two glutaminase isoforms namely, the kidney isoform (KGA or GLS1) and the liver isoform (LGA or GLS2). The evidence accumulated so far suggests that KGA and particularly its splice variant GAC are targets of interest for cancer therapy. KGA/GAC upregulation is present in multiple cancer cell lines, correlates with increased proliferative rates, and it is linked to the dysregulation of a number of pathways, including the dysregulation/amplification of the Myc oncogene. Inhibition of KGA/GAC through antisense, siRNA and small molecule inhibitors leads to reduction in tumor cell proliferation as well as tumor size reduction in mice.